Hypercholesterolemia Promotes P-Selectin–Dependent Platelet–Endothelial Cell Adhesion in Postcapillary Venules

Tailor, Anitaben; Granger, D. Neil

doi:10.1161/01.atv.0000056742.97580.79

Cited by 81 publications

(81 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Platelets were isolated from whole blood by a series of centrifugation steps, labeled with the fluorochrome carboxyfluorescein diacetate succinimudyl ester (CFSE; Molecular Probes, Eugene OR) as described previously [17], and resuspended in PBS at a concentration of 8.33 ×10 5 cells/μl. This technique does not cause platelet activation as determined by P-selectin expression using flow-cytometry [13]. Before infusion, it was confirmed with the aid of a hemocytometer that there was no leukocyte contamination of the platelet suspension.…”

Section: Surgical Protocolmentioning

confidence: 86%

“…The hypercholesterolemia-induced leukocyte adhesion involves superoxide generated from NAD(P)H oxidase that is expressed in the vessel wall as well as circulating blood cells. The hypercholesterolemia-induced platelet accumulation in venules is a P-selectin-dependent process [4,13] that appears to result from an interaction between P-selectin on platelets and PSGL-1 on adherent leukocytes, with direct interactions between platelets and the vascular endothelium accounting for only a small portion of platelet recruitment [4,14]. Although NAD (P)H oxidase has been implicated in the recruitment of platelets during hypercholesterolemia, the relative importance of leukocyte-, endothelial-and platelet-associated forms of NAD(P)H oxidase in this process remains unclear.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia

Stokes

Russell

Jennings

et al. 2007

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Elevated cholesterol levels promote pro-inflammatory and prothrombogenic responses in venules and impaired endothelium-dependent arteriolar dilation. Although NAD(P)H oxidase-derived superoxide has been implicated in the altered vascular responses to hypercholesterolemia, it remains unclear whether this oxidative pathway mediates the associated arteriolar dysfunction and platelet adhesion in venules. Platelet and leukocyte adhesion in cremasteric postcapillary venules, and arteriolar dilation responses to acetylcholine were monitored in wild-type (WT), Cu,Zn-superoxide dismutase transgenic (SOD-TgN) and NAD(P)H oxidase-knockout (gp91 phox-/-) mice placed on normal (ND) or high cholesterol (HC) diet for 2 wk. HC elicited increased platelet and leukocyte adhesion in WT mice, versus ND. Cytosolic subunits of NAD(P)H oxidase (p47phox and p67phox) were expressed in platelets. This was not altered by hypercholesterolemia, however platelets and leukocytes from HC mice exhibited elevated generation of reactive oxygen species when compared to ND mice. Hypercholesterolemia-induced leukocyte recruitment was attenuated in SOD-TgN-HC and gp91 phox-/--HC mice. Recruitment of platelets derived from WT-HC mice in venules of SODTgN-HC or gp91 phox-/--HC recipients was comparable to ND levels. Adhesion of SOD-TgN-HC platelets paralleled the leukocyte response and was attenuated in SOD-TgN-HC recipients, but not in WT-HC recipients. However, gp91 phox-/--HC platelets exhibited low levels of adhesion comparable to WT-ND in both hypercholesterolemic gp91 phox-/-and WT recipients. Arteriolar dysfunction was evident in WT-HC mice, compared to WT-ND. Overexpression of SOD or, to a lesser extent, gp91 phox deficiency, restored arteriolar vasorelaxation responses towards WT-ND levels. These findings reveal a novel role for platelet-associated NAD(P)H oxidase in producing the thrombogenic phenotype in hypercholesterolemia and demonstrate that NAD(P)H oxidase-derived superoxide mediates the HC-induced arteriolar dysfunction.

show abstract

Section: Surgical Protocolmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia

Stokes

Russell

Jennings

et al. 2007

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…To confirm BM reconstitution, platelets were isolated and assessed for expression of P-selectin under activating conditions via flow cytometry. 42 …”

Section: Generation Of Bone Marrow Chimerasmentioning

confidence: 99%

Platelet Recruitment to the Inflamed Glomerulus Occurs via an αIIbβ3/GPVI-Dependent Pathway

Devi

Kuligowski

Kwan

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Recruitment of leukocytes to glomeruli is fundamental to the pathogenesis of many forms of glomerulonephritis. In a model of glomerulonephritis induced by in situ immune complex deposition, we previously observed that, in addition to leukocytes, platelets accumulate in glomerular capillaries, where they contribute to leukocyte recruitment. However, the mechanisms of platelet recruitment and the role of platelet-expressed P-selectin in leukocyte recruitment require further investigation. We used intravital microscopy to examine the mechanisms of platelet and leukocyte recruitment to glomeruli of mice following administration of an antibody against the glomerular basement membrane (anti-GBM antibody). Platelet recruitment was initiated within five minutes of administration of anti-GBM antibody. This was unaltered by inhibition of platelet GPIb␣ but was prevented by the absence of platelet GPVI. Fibrinogen was deposited in glomerular capillaries via a partially intercellular adhesion molecule 1 (ICAM-1)-dependent mechanism, and inhibition of ␣ IIb ␤ 3 , fibrinogen and ICAM-1 inhibited platelet recruitment. Notably, neutrophil depletion also reduced platelet accumulation, indicating a cooperative interaction underlying recruitment of platelets and neutrophils. Finally, using bone marrow chimeras to restrict expression of P-selectin to platelets or endothelial cells, platelet but not endothelial P-selectin was required for glomerular leukocyte recruitment. Together these data indicate that platelet recruitment in this model is dependent on the combined actions of GPVI and the ␣ IIb ␤ 3 /fibrinogen/ ICAM-1 pathway and that platelet P-selectin is crucial for subsequent leukocyte recruitment. (Am J Pathol

show abstract

“…P-selectin is a key cell adhesion molecule involved in mediating the recruitment, rolling, and interaction of leukocytes (and platelets) under inflammatory conditions through its ligand P-selectin glycoprotein ligand-1 (PSGL-1). [41][42][43][44] These interactions likely contribute to impaired vascular function in IR injury as well as other vasculopathies as well. 45,46 Kupffer cells also can contribute to IR injury through their ability to produce cytokines and reactive oxygen species (ROS) which contributes to SEC apoptosis.…”

Section: Ischemia and Reperfusion Injurymentioning

confidence: 99%

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

2008

View full text Add to dashboard Cite

Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Vascular Cell Signaling Mediated by NO. Endothelial cells (ECs) produce NO through the enzyme endothelial NO synthase (eNOS). NO then regulates important vascular functions, such as vascular tone, angiogenesis, and arterial remodeling. 1 eNOS is regulated in a multiprotein complex (Fig. 1), which includes the activating kinase, Akt1 and putative negative regulator caveolin-1 (Cav-1). Although eNOS Ϫ/Ϫ mice evidence impaired angiogenesis, overexpression of a constitutively active allele of eNOS that mimics the phosphorylated and active state rescues these angiogenic defects. 2 Because eNOS is an EC-specific Akt substrate, ECs from mice lacking the Akt1 isoform also have defects in eNOS phosphorylation, NO production, and angiogenesis which are correspondingly rescued by Akt1 overexpression. 3 One key mechanism by which the Akt-eNOS axis promotes angiogenesis in vivo is through mobilization of endothelial progenitor cells and EC migration to sites of vascular injury. In contradistinction to AKT, Cav-1 is a negative regulator of eNOS. Mice deficient in Cav-1 have defective mechanotransduction, calcium signaling, prostacyclin production, and elevated NO production indicating that endothelial Cav-1 also importantly regulates vascular function by regulating eNOS and other signaling pathways. 4 Upon its generation in ECs, NO also acts on adjacent vascular effector cells to modulate vascular tone, cellular proliferation, apoptosis, migration, and synthesis of extracellular matrix (Fig. 2). NO acts in part by stimulating soluble guanylate cyclase (sGC) to produce intracellular Abbreviations: Cav-

show abstract

Hypercholesterolemia Promotes P-Selectin–Dependent Platelet–Endothelial Cell Adhesion in Postcapillary Venules

Cited by 81 publications

References 59 publications

Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia

Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia

Platelet Recruitment to the Inflamed Glomerulus Occurs via an αIIbβ3/GPVI-Dependent Pathway

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

Contact Info

Product

Resources

About